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Unusual Casts in a Case of Multiple Myeloma

2009; Elsevier BV; Volume: 54; Issue: 5 Linguagem: Inglês

10.1053/j.ajkd.2009.01.273

1523-6838

Sanjeev Sethi, Matthew H. Hanna, Fernando C. Fervenza,

Myeloproliferative Neoplasms: Diagnosis and Treatment

Multiple myeloma and lymphoproliferative disorders often cause kidney disease. The spectrum of associated kidney diseases includes myeloma kidney (cast nephropathy), amyloidosis, and monoclonal immunoglobulin deposition disease.1Schwartz M.M. The dysproteinemias and amyloidosis.in: Jennette J.C. Olsen J.L. Schwartz M.M. Silva F.G. Heptinstall's Pathology of the Kidney. (ed 5). Lippincott-Raven, Philadelphia, PA1998Google Scholar Cast nephropathy is the most common form. We present interesting biopsy findings in a patient with multiple myeloma who presented with kidney failure.Case ReportClinical HistoryA 59-year-old woman with a history of hypertension and gastroesophageal reflux disease presented to the emergency department with a 1-week history of numbness, tingling, and burning sensation in her arms. She also had significant midback pain for months that had increased during the last week. She also reported generalized fatigue. The patient denied fevers, rashes, weight loss, night sweats, or visual changes. There was no history of chest pain, palpitations, abdominal bloating, shortness of breath, or hemoptysis. In recent months, she was using nonsteroidal anti inflammatory drugs for the backache. Other medications included valsartan and amlodipine. In view of her unexplained symptoms, she was admitted to the hospital for workup.On examination, the patient appeared ill. She weighed 159 pounds with a body mass index of 27.3 kg/m2. Heart rate was 80 beats/min and regular, and blood pressure was 115/60 mm Hg. Lungs were clear to auscultation. She had normal heart sounds with no murmurs. Her abdomen was soft and nontender, with no organomegaly. Her sensation was uniformly normal, but she had weakness in all extremities.Serum creatinine level at admission was 9.5 mg/dL (840 μmol/L), with an estimated glomerular filtration rate of 8 mL/min (0.133 mL/s) and blood urea nitrogen level was 100 mg/dL (35.7 mmol/L). Laboratory findings are listed in Table 1. Radiographs of the spine showed multifocal compressive fractures suggestive of osteopenia and malignancy. Bone survey showed multiple lesions in the entire skeletal system with compression deformity at C3, C8, and T10 to T11. There were multiple osteolytic lesions in the pelvis, ribs, and long bones; healed fractures; and a large lesion at L3. The initial impression was that of multiple myeloma based on the findings of normochromic anemia, increased erythrocyte sedimentation rate, acute kidney injury, and compressive spine fractures. Kidney biopsy was performed to determine the cause of kidney injury.Table 1Laboratory ResultsSerum creatinine (mg/dL)9.5Blood urea nitrogen (mg/dL)100Estimated GFR (mL/min; 4-point Modification of Diet and Renal Disease Study equation)8Erythrocyte sedimentation rate (mm/1 h)64Serum total protein (g/dL)4.7Serum albumin (g/dL)2.7Hemoglobin (g/dL)8.6Hematocrit (%)26Mean corpuscular volume (fl)90White blood cell count (× 103/μL)822Platelet count (× 103/μL)224Blood glucose (mg/dL)102Serum calcium (mg/dL)7.4Sodium (mEq/L)134Potassium (mEq/L)3.9Uric acid (mg/dL)10.2Ionized calcium (mg/dL)1.42Urinalysis3+ protein, trace red blood cells, no castsNote: Conversion factors for units: serum sodium and potassium levels expressed in mEq/L and mmol/L are equivalent; blood urea nitrogen in mg/dL to mmol/L, ×0.357; GFR in mL/min to mL/s, ×0.01667; creatinine in mg/dL to μmol/L, ×88.4; albumin, protein, and hemoglobin in g/dL to g/L, ×10; total bilirubin in mg/dL to μmol/L, ×17.1; platelets and white blood cell count in × 103/μL and × 103/L are equivalent; glucose in mg/dL to mmol/L, ×0.0551; calcium in mg/dL to mmol/L, ×0.2495; uric acid in mg/dL to μmol/L, ×59.48; calcium ion in mEq/L to mmol/L, ×0.5.Abbreviation: GFR, glomerular filtration rate. Open table in a new tab Kidney BiopsyTissue submitted for light microscopy contained 4 cores. Both medulla and cortex were present. There were 14 glomeruli present, 1 of which was globally sclerosed. Glomeruli appeared unremarkable. In particular, glomeruli did not show evidence of mesangial expansion, and mesangial nodules were not present. Capillary loops were patent. Glomerular basement membranes were not thickened. Double contours, basement membrane spikes, or pinholes were not present. The interstitium showed features of myeloma kidney (cast nephropathy). Typical features of cast nephropathy were present, which included weakly positive periodic acid–Schiff (PAS)- and silver-negative casts with a "fractured" appearance surrounded by a cellular inflammatory reaction that included mononuclear cells and occasionally giant cells (Fig 1A and B). The diagnosis was confirmed by using immunofluorescence microscopy, which showed that casts stained intensely for λ light chains, but were negative for κ light chains (Fig 1C and D).However, in this case, there were many casts that appeared lamellated and had spicules imparting a hairy appearance, with surrounding inflammatory cells in layers (Fig 2A to D). Oddly, these casts were intensely silver positive (myeloma casts usually are silver negative). The casts appeared to a have central nidus of necrotic and cellular debris. Congo red stain showed that these casts were positive for amyloid and showed apple green birefringence under polarized light (Fig 2E). Congo red stains of myeloma casts were negative. In addition, Congo red stains were negative in glomeruli, interstitium, and vessel walls. The interstitium showed moderately extensive (60%) tubular atrophy and interstitial fibrosis. Arteries and arterioles appeared unremarkable. Electron microscopy confirmed 2 types of casts. Casts with features of cast nephropathy showed intensely osmiophilic necrotic material in the lumen, whereas casts that were Congo red positive consisted of amyloid fibrils and showed the spicule formation (Fig 2F). The spicules noted on light microscopy were arrays of amyloid fibrils. The fibrils measured 9.5 nm in diameter. Surprisingly, there was no amyloid present in glomeruli or vessel walls. In addition, such features of light chain deposit disease as fine granular deposits along the glomerular or tubular basement membranes were not present.Figure 2(A, B) Trichrome, (C) PAS, and (D) silver stains show tubular casts with spicules and surrounding inflammatory cells (A, B: original magnification: A, ×10; B, D, ×40; C, ×60). (E) Congo red stains show that the casts are Congo red positive (original magnification ×60), and (F) electron microscopy confirmed the diagnosis of tubular amyloid (original magnification ×4,200).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Diagnosis(1) Cast nephropathy (myeloma kidney), λ light chain type; and (2) tubular amyloidosis, AL type, λ light chain type.Clinical Follow-upBone marrow aspirate showed 90% plasma cells. Bone marrow biopsy showed a predominant population of λ light chain–restricted plasma cells, consistent with multiple myeloma. Congo red stains on the bone marrow biopsy specimen were negative for amyloid. The patient was referred to an academic medical center and was being considered for autologous stem cell transplantation.DiscussionWe present a case of acute kidney injury in a 59-year-old woman who presented to the emergency department with backaches and numbness and tingling of her limbs. Subsequent workup showed multiple myeloma with extensive involvement of the skeletal system. The initial clinical impression of the acute kidney injury was that of myeloma kidney (cast nephropathy) or interstitial nephritis secondary to nonsteroidal anti inflammatory drug use. Kidney biopsy specimens showed features of cast nephropathy with PAS- and silver-negative casts with a fractured appearance surrounded by an interstitial infiltrate. The diagnosis of cast nephropathy was confirmed on immunofluorescence microscopy, in which many casts stained for λ light chains, but were negative for κ light chains. However, the case was unusual in that some casts did not appear to be histologically like those in cast nephropathy, although they elicited an inflammatory reaction around them. These casts were PAS and silver positive, appeared lamellated with a central necrotic nidus, and some casts showed distinct spicule formation on their periphery. In addition, casts were much larger, did not have a fractured appearance, and showed bright apple green birefringence on Congo red stains, suggesting they were made of amyloid fibrils. Electron microscopy confirmed that these casts were made of amyloid fibrils.Amyloid can be found anywhere in the kidney, but glomerular deposition typically predominates. By using light microscopy, glomerular amyloid appears as amorphous material in the mesangium and capillary loops. Mesangial involvement usually leads to the formation of PAS-negative mesangial nodules. Glomerular capillary walls are infiltrated with amyloid, resulting in thickening of glomerular basement membranes. On silver stains, spicules can be seen at the periphery of the amyloid material both in the mesangium and along capillary walls. When the glomerulus is involved, almost 50% of patients present with reduced glomerular filtration rate and more than 70% have proteinuria. Vessels also are commonly involved, initially in the media. Less commonly, amyloid deposits in the tubular basement membrane lead to tubular atrophy and interstitial fibrosis. When amyloid is confined to the tubulointerstitium or vasculature, a concentrating defect may be present, and proteinuria is minimal and reduced glomerular filtration rate is the principal clinical manifestation.2Dember L.M. Amyloidosis-associated kidney disease.J Am Soc Nephrol. 2006; 17: 3458-3471Crossref PubMed Scopus (265) Google Scholar, 3Kyle R.A. Greipp P.R. Amyloidosis (AL) Clinical and laboratory features in 229 cases.Mayo Clin Proc. 1983; 58: 665-683PubMed Google Scholar, 4Gertz M.A. Lacy M.Q. Dispenzieri A. Amyloidosis: Recognition, confirmation, prognosis, and therapy.Mayo Clin Proc. 1999; 74: 490-494PubMed Scopus (99) Google ScholarA search of the literature showed 3 reports of amyloid casts in tubules.5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar, 6El-Zoghby Z. Lager D. Gregoire J. Lewin M. Sethi S. Intra-tubular amyloidosis.Kidney Int. 2007; 72: 1282-1288Crossref PubMed Scopus (23) Google Scholar, 7Friman C. Tornroth T. Wegelius O. IgD myeloma associated with multiple extramedullary amyloid-containing tumours and amyloid casts in the renal tubules.Ann Clin Res. 1970; 2: 161-166PubMed Google Scholar Melato et al5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar examined 30 autopsy specimens from patients who had multiple myeloma or monoclonal gammopathy of undetermined significance. They found 4 cases of renal tubular casts showing histochemical characteristics of immunoamyloid. All patients had multiple myeloma with light chains in urine. No case of monoclonal gammopathy had tubular amyloid casts.5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar The diagnosis of tubular amyloid casts was based on Congo red stains. Because tissue was obtained from autopsy specimens, immunofluorescence and electron microscopy were not carried out. El-Zoghby et al6El-Zoghby Z. Lager D. Gregoire J. Lewin M. Sethi S. Intra-tubular amyloidosis.Kidney Int. 2007; 72: 1282-1288Crossref PubMed Scopus (23) Google Scholar also reported a case of intratubular amyloid casts in a patient with multiple myeloma. The case is similar to our case in that amyloid casts were noted in tubules, whereas glomeruli and vessels did not show amyloid. Friman et al7Friman C. Tornroth T. Wegelius O. IgD myeloma associated with multiple extramedullary amyloid-containing tumours and amyloid casts in the renal tubules.Ann Clin Res. 1970; 2: 161-166PubMed Google Scholar reported a case of immunoglobulin D myeloma associated with multiple extramedullary amyloid-containing tumors and amyloid casts in renal tubules.Differential diagnosis of casts in a setting of multiple myeloma includes: (1) myeloma casts: fractured casts of myeloma kidney/cast nephropathy as described; (2) hyaline casts: these casts are PAS and silver positive, often present in tubules in scarred areas, do not show a preference for κ or λ light chains, and often stain for immunoglobulin A on immunofluorescence microscopy; they do not elicit an inflammatory reaction; (3) Tamm-Horsfall protein casts: often seen in the setting of obstruction, with leakage of casts into the interstitium with localized inflammatory infiltrates; (4) light chain crystal casts: often seen in patients with Fanconi syndrome or crystal-storing histiocytosis,8Sethi S. Cuiffo B. Pinkus G. Rennke H. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder.Am J Kidney Dis. 2002; 39: 183-188Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar casts are PAS positive and have needle, rectangular, or rhomboid appearance; are present in tubular lumen and tubular epithelial cells; and stain for either λ or κ light chains on immunofluorescence microscopy; and (5) AL amyloid casts: casts are PAS and silver negative, may have spicule formation at the rims, are Congo red positive, and electron microscopy confirms the diagnosis (Table 2).Table 2Casts in Multiple MyelomaMyeloma castsFractured appearance, PAS and silver negative, surrounded by inflammatory infiltrate, positive for either κ or λ light chainsHyaline castsHomogenous appearance, PAS and silver positive, often present in scarred areas, stain for polyclonal IgATamm-Horsfall protein castsLarge amorphous-appearing, tubular disruption leads to leakage of casts into interstitium and localized inflammatory infiltrates, PAS positive or negative, polyclonalLight chain crystal castsNeedle, rectangular, or rhomboid appearance; PAS positive; present in tubular lumen and tubular epithelial cells; positive for either λ or κ light chainsLight chain amyloid castsMay have spicule formation at rims with necrotic center, PAS and silver negative, Congo red positive, positive for either κ or λ light chains, electron microscopy confirms diagnosisAbbreviations: IgA, immunoglobulin A; PAS, periodic acid–Schiff. Open table in a new tab The pathophysiological process of intratubular amyloid is unclear because amyloid fibrils are large and likely not filtered through the glomerular basement membrane. One has to assume that fibrils are formed inside the tubule from either protein secreted by tubular cells or filtered light chains. The latter is more likely because it is the mechanism by which intratubular casts are formed in patients with multiple myeloma.9Sanders P.W. Herrera G.A. Monoclonal immunoglobulin light chain-related renal diseases.Semin Nephrol. 1993; 13: 324-341PubMed Google Scholar, 10Palladini G. Lavatelli F. Russo P. et al.Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL.Blood. 2006; 107: 3854-3858Crossref PubMed Scopus (220) Google ScholarTo summarize, we present an interesting case of multiple myeloma with features of both cast nephropathy and tubular amyloid casts. Although cast nephropathy with glomerular amyloid has been described, the presentation of both myeloma casts and tubular amyloid casts together is unusual. Amyloid casts should be considered when differentiating casts in a setting of multiple myeloma. Multiple myeloma and lymphoproliferative disorders often cause kidney disease. The spectrum of associated kidney diseases includes myeloma kidney (cast nephropathy), amyloidosis, and monoclonal immunoglobulin deposition disease.1Schwartz M.M. The dysproteinemias and amyloidosis.in: Jennette J.C. Olsen J.L. Schwartz M.M. Silva F.G. Heptinstall's Pathology of the Kidney. (ed 5). Lippincott-Raven, Philadelphia, PA1998Google Scholar Cast nephropathy is the most common form. We present interesting biopsy findings in a patient with multiple myeloma who presented with kidney failure. Case ReportClinical HistoryA 59-year-old woman with a history of hypertension and gastroesophageal reflux disease presented to the emergency department with a 1-week history of numbness, tingling, and burning sensation in her arms. She also had significant midback pain for months that had increased during the last week. She also reported generalized fatigue. The patient denied fevers, rashes, weight loss, night sweats, or visual changes. There was no history of chest pain, palpitations, abdominal bloating, shortness of breath, or hemoptysis. In recent months, she was using nonsteroidal anti inflammatory drugs for the backache. Other medications included valsartan and amlodipine. In view of her unexplained symptoms, she was admitted to the hospital for workup.On examination, the patient appeared ill. She weighed 159 pounds with a body mass index of 27.3 kg/m2. Heart rate was 80 beats/min and regular, and blood pressure was 115/60 mm Hg. Lungs were clear to auscultation. She had normal heart sounds with no murmurs. Her abdomen was soft and nontender, with no organomegaly. Her sensation was uniformly normal, but she had weakness in all extremities.Serum creatinine level at admission was 9.5 mg/dL (840 μmol/L), with an estimated glomerular filtration rate of 8 mL/min (0.133 mL/s) and blood urea nitrogen level was 100 mg/dL (35.7 mmol/L). Laboratory findings are listed in Table 1. Radiographs of the spine showed multifocal compressive fractures suggestive of osteopenia and malignancy. Bone survey showed multiple lesions in the entire skeletal system with compression deformity at C3, C8, and T10 to T11. There were multiple osteolytic lesions in the pelvis, ribs, and long bones; healed fractures; and a large lesion at L3. The initial impression was that of multiple myeloma based on the findings of normochromic anemia, increased erythrocyte sedimentation rate, acute kidney injury, and compressive spine fractures. Kidney biopsy was performed to determine the cause of kidney injury.Table 1Laboratory ResultsSerum creatinine (mg/dL)9.5Blood urea nitrogen (mg/dL)100Estimated GFR (mL/min; 4-point Modification of Diet and Renal Disease Study equation)8Erythrocyte sedimentation rate (mm/1 h)64Serum total protein (g/dL)4.7Serum albumin (g/dL)2.7Hemoglobin (g/dL)8.6Hematocrit (%)26Mean corpuscular volume (fl)90White blood cell count (× 103/μL)822Platelet count (× 103/μL)224Blood glucose (mg/dL)102Serum calcium (mg/dL)7.4Sodium (mEq/L)134Potassium (mEq/L)3.9Uric acid (mg/dL)10.2Ionized calcium (mg/dL)1.42Urinalysis3+ protein, trace red blood cells, no castsNote: Conversion factors for units: serum sodium and potassium levels expressed in mEq/L and mmol/L are equivalent; blood urea nitrogen in mg/dL to mmol/L, ×0.357; GFR in mL/min to mL/s, ×0.01667; creatinine in mg/dL to μmol/L, ×88.4; albumin, protein, and hemoglobin in g/dL to g/L, ×10; total bilirubin in mg/dL to μmol/L, ×17.1; platelets and white blood cell count in × 103/μL and × 103/L are equivalent; glucose in mg/dL to mmol/L, ×0.0551; calcium in mg/dL to mmol/L, ×0.2495; uric acid in mg/dL to μmol/L, ×59.48; calcium ion in mEq/L to mmol/L, ×0.5.Abbreviation: GFR, glomerular filtration rate. Open table in a new tab Kidney BiopsyTissue submitted for light microscopy contained 4 cores. Both medulla and cortex were present. There were 14 glomeruli present, 1 of which was globally sclerosed. Glomeruli appeared unremarkable. In particular, glomeruli did not show evidence of mesangial expansion, and mesangial nodules were not present. Capillary loops were patent. Glomerular basement membranes were not thickened. Double contours, basement membrane spikes, or pinholes were not present. The interstitium showed features of myeloma kidney (cast nephropathy). Typical features of cast nephropathy were present, which included weakly positive periodic acid–Schiff (PAS)- and silver-negative casts with a "fractured" appearance surrounded by a cellular inflammatory reaction that included mononuclear cells and occasionally giant cells (Fig 1A and B). The diagnosis was confirmed by using immunofluorescence microscopy, which showed that casts stained intensely for λ light chains, but were negative for κ light chains (Fig 1C and D).However, in this case, there were many casts that appeared lamellated and had spicules imparting a hairy appearance, with surrounding inflammatory cells in layers (Fig 2A to D). Oddly, these casts were intensely silver positive (myeloma casts usually are silver negative). The casts appeared to a have central nidus of necrotic and cellular debris. Congo red stain showed that these casts were positive for amyloid and showed apple green birefringence under polarized light (Fig 2E). Congo red stains of myeloma casts were negative. In addition, Congo red stains were negative in glomeruli, interstitium, and vessel walls. The interstitium showed moderately extensive (60%) tubular atrophy and interstitial fibrosis. Arteries and arterioles appeared unremarkable. Electron microscopy confirmed 2 types of casts. Casts with features of cast nephropathy showed intensely osmiophilic necrotic material in the lumen, whereas casts that were Congo red positive consisted of amyloid fibrils and showed the spicule formation (Fig 2F). The spicules noted on light microscopy were arrays of amyloid fibrils. The fibrils measured 9.5 nm in diameter. Surprisingly, there was no amyloid present in glomeruli or vessel walls. In addition, such features of light chain deposit disease as fine granular deposits along the glomerular or tubular basement membranes were not present.Diagnosis(1) Cast nephropathy (myeloma kidney), λ light chain type; and (2) tubular amyloidosis, AL type, λ light chain type.Clinical Follow-upBone marrow aspirate showed 90% plasma cells. Bone marrow biopsy showed a predominant population of λ light chain–restricted plasma cells, consistent with multiple myeloma. Congo red stains on the bone marrow biopsy specimen were negative for amyloid. The patient was referred to an academic medical center and was being considered for autologous stem cell transplantation. Clinical HistoryA 59-year-old woman with a history of hypertension and gastroesophageal reflux disease presented to the emergency department with a 1-week history of numbness, tingling, and burning sensation in her arms. She also had significant midback pain for months that had increased during the last week. She also reported generalized fatigue. The patient denied fevers, rashes, weight loss, night sweats, or visual changes. There was no history of chest pain, palpitations, abdominal bloating, shortness of breath, or hemoptysis. In recent months, she was using nonsteroidal anti inflammatory drugs for the backache. Other medications included valsartan and amlodipine. In view of her unexplained symptoms, she was admitted to the hospital for workup.On examination, the patient appeared ill. She weighed 159 pounds with a body mass index of 27.3 kg/m2. Heart rate was 80 beats/min and regular, and blood pressure was 115/60 mm Hg. Lungs were clear to auscultation. She had normal heart sounds with no murmurs. Her abdomen was soft and nontender, with no organomegaly. Her sensation was uniformly normal, but she had weakness in all extremities.Serum creatinine level at admission was 9.5 mg/dL (840 μmol/L), with an estimated glomerular filtration rate of 8 mL/min (0.133 mL/s) and blood urea nitrogen level was 100 mg/dL (35.7 mmol/L). Laboratory findings are listed in Table 1. Radiographs of the spine showed multifocal compressive fractures suggestive of osteopenia and malignancy. Bone survey showed multiple lesions in the entire skeletal system with compression deformity at C3, C8, and T10 to T11. There were multiple osteolytic lesions in the pelvis, ribs, and long bones; healed fractures; and a large lesion at L3. The initial impression was that of multiple myeloma based on the findings of normochromic anemia, increased erythrocyte sedimentation rate, acute kidney injury, and compressive spine fractures. Kidney biopsy was performed to determine the cause of kidney injury.Table 1Laboratory ResultsSerum creatinine (mg/dL)9.5Blood urea nitrogen (mg/dL)100Estimated GFR (mL/min; 4-point Modification of Diet and Renal Disease Study equation)8Erythrocyte sedimentation rate (mm/1 h)64Serum total protein (g/dL)4.7Serum albumin (g/dL)2.7Hemoglobin (g/dL)8.6Hematocrit (%)26Mean corpuscular volume (fl)90White blood cell count (× 103/μL)822Platelet count (× 103/μL)224Blood glucose (mg/dL)102Serum calcium (mg/dL)7.4Sodium (mEq/L)134Potassium (mEq/L)3.9Uric acid (mg/dL)10.2Ionized calcium (mg/dL)1.42Urinalysis3+ protein, trace red blood cells, no castsNote: Conversion factors for units: serum sodium and potassium levels expressed in mEq/L and mmol/L are equivalent; blood urea nitrogen in mg/dL to mmol/L, ×0.357; GFR in mL/min to mL/s, ×0.01667; creatinine in mg/dL to μmol/L, ×88.4; albumin, protein, and hemoglobin in g/dL to g/L, ×10; total bilirubin in mg/dL to μmol/L, ×17.1; platelets and white blood cell count in × 103/μL and × 103/L are equivalent; glucose in mg/dL to mmol/L, ×0.0551; calcium in mg/dL to mmol/L, ×0.2495; uric acid in mg/dL to μmol/L, ×59.48; calcium ion in mEq/L to mmol/L, ×0.5.Abbreviation: GFR, glomerular filtration rate. Open table in a new tab A 59-year-old woman with a history of hypertension and gastroesophageal reflux disease presented to the emergency department with a 1-week history of numbness, tingling, and burning sensation in her arms. She also had significant midback pain for months that had increased during the last week. She also reported generalized fatigue. The patient denied fevers, rashes, weight loss, night sweats, or visual changes. There was no history of chest pain, palpitations, abdominal bloating, shortness of breath, or hemoptysis. In recent months, she was using nonsteroidal anti inflammatory drugs for the backache. Other medications included valsartan and amlodipine. In view of her unexplained symptoms, she was admitted to the hospital for workup. On examination, the patient appeared ill. She weighed 159 pounds with a body mass index of 27.3 kg/m2. Heart rate was 80 beats/min and regular, and blood pressure was 115/60 mm Hg. Lungs were clear to auscultation. She had normal heart sounds with no murmurs. Her abdomen was soft and nontender, with no organomegaly. Her sensation was uniformly normal, but she had weakness in all extremities. Serum creatinine level at admission was 9.5 mg/dL (840 μmol/L), with an estimated glomerular filtration rate of 8 mL/min (0.133 mL/s) and blood urea nitrogen level was 100 mg/dL (35.7 mmol/L). Laboratory findings are listed in Table 1. Radiographs of the spine showed multifocal compressive fractures suggestive of osteopenia and malignancy. Bone survey showed multiple lesions in the entire skeletal system with compression deformity at C3, C8, and T10 to T11. There were multiple osteolytic lesions in the pelvis, ribs, and long bones; healed fractures; and a large lesion at L3. The initial impression was that of multiple myeloma based on the findings of normochromic anemia, increased erythrocyte sedimentation rate, acute kidney injury, and compressive spine fractures. Kidney biopsy was performed to determine the cause of kidney injury. Note: Conversion factors for units: serum sodium and potassium levels expressed in mEq/L and mmol/L are equivalent; blood urea nitrogen in mg/dL to mmol/L, ×0.357; GFR in mL/min to mL/s, ×0.01667; creatinine in mg/dL to μmol/L, ×88.4; albumin, protein, and hemoglobin in g/dL to g/L, ×10; total bilirubin in mg/dL to μmol/L, ×17.1; platelets and white blood cell count in × 103/μL and × 103/L are equivalent; glucose in mg/dL to mmol/L, ×0.0551; calcium in mg/dL to mmol/L, ×0.2495; uric acid in mg/dL to μmol/L, ×59.48; calcium ion in mEq/L to mmol/L, ×0.5. Abbreviation: GFR, glomerular filtration rate. Kidney BiopsyTissue submitted for light microscopy contained 4 cores. Both medulla and cortex were present. There were 14 glomeruli present, 1 of which was globally sclerosed. Glomeruli appeared unremarkable. In particular, glomeruli did not show evidence of mesangial expansion, and mesangial nodules were not present. Capillary loops were patent. Glomerular basement membranes were not thickened. Double contours, basement membrane spikes, or pinholes were not present. The interstitium showed features of myeloma kidney (cast nephropathy). Typical features of cast nephropathy were present, which included weakly positive periodic acid–Schiff (PAS)- and silver-negative casts with a "fractured" appearance surrounded by a cellular inflammatory reaction that included mononuclear cells and occasionally giant cells (Fig 1A and B). The diagnosis was confirmed by using immunofluorescence microscopy, which showed that casts stained intensely for λ light chains, but were negative for κ light chains (Fig 1C and D).However, in this case, there were many casts that appeared lamellated and had spicules imparting a hairy appearance, with surrounding inflammatory cells in layers (Fig 2A to D). Oddly, these casts were intensely silver positive (myeloma casts usually are silver negative). The casts appeared to a have central nidus of necrotic and cellular debris. Congo red stain showed that these casts were positive for amyloid and showed apple green birefringence under polarized light (Fig 2E). Congo red stains of myeloma casts were negative. In addition, Congo red stains were negative in glomeruli, interstitium, and vessel walls. The interstitium showed moderately extensive (60%) tubular atrophy and interstitial fibrosis. Arteries and arterioles appeared unremarkable. Electron microscopy confirmed 2 types of casts. Casts with features of cast nephropathy showed intensely osmiophilic necrotic material in the lumen, whereas casts that were Congo red positive consisted of amyloid fibrils and showed the spicule formation (Fig 2F). The spicules noted on light microscopy were arrays of amyloid fibrils. The fibrils measured 9.5 nm in diameter. Surprisingly, there was no amyloid present in glomeruli or vessel walls. In addition, such features of light chain deposit disease as fine granular deposits along the glomerular or tubular basement membranes were not present. Tissue submitted for light microscopy contained 4 cores. Both medulla and cortex were present. There were 14 glomeruli present, 1 of which was globally sclerosed. Glomeruli appeared unremarkable. In particular, glomeruli did not show evidence of mesangial expansion, and mesangial nodules were not present. Capillary loops were patent. Glomerular basement membranes were not thickened. Double contours, basement membrane spikes, or pinholes were not present. The interstitium showed features of myeloma kidney (cast nephropathy). Typical features of cast nephropathy were present, which included weakly positive periodic acid–Schiff (PAS)- and silver-negative casts with a "fractured" appearance surrounded by a cellular inflammatory reaction that included mononuclear cells and occasionally giant cells (Fig 1A and B). The diagnosis was confirmed by using immunofluorescence microscopy, which showed that casts stained intensely for λ light chains, but were negative for κ light chains (Fig 1C and D). However, in this case, there were many casts that appeared lamellated and had spicules imparting a hairy appearance, with surrounding inflammatory cells in layers (Fig 2A to D). Oddly, these casts were intensely silver positive (myeloma casts usually are silver negative). The casts appeared to a have central nidus of necrotic and cellular debris. Congo red stain showed that these casts were positive for amyloid and showed apple green birefringence under polarized light (Fig 2E). Congo red stains of myeloma casts were negative. In addition, Congo red stains were negative in glomeruli, interstitium, and vessel walls. The interstitium showed moderately extensive (60%) tubular atrophy and interstitial fibrosis. Arteries and arterioles appeared unremarkable. Electron microscopy confirmed 2 types of casts. Casts with features of cast nephropathy showed intensely osmiophilic necrotic material in the lumen, whereas casts that were Congo red positive consisted of amyloid fibrils and showed the spicule formation (Fig 2F). The spicules noted on light microscopy were arrays of amyloid fibrils. The fibrils measured 9.5 nm in diameter. Surprisingly, there was no amyloid present in glomeruli or vessel walls. In addition, such features of light chain deposit disease as fine granular deposits along the glomerular or tubular basement membranes were not present. Diagnosis(1) Cast nephropathy (myeloma kidney), λ light chain type; and (2) tubular amyloidosis, AL type, λ light chain type. (1) Cast nephropathy (myeloma kidney), λ light chain type; and (2) tubular amyloidosis, AL type, λ light chain type. Clinical Follow-upBone marrow aspirate showed 90% plasma cells. Bone marrow biopsy showed a predominant population of λ light chain–restricted plasma cells, consistent with multiple myeloma. Congo red stains on the bone marrow biopsy specimen were negative for amyloid. The patient was referred to an academic medical center and was being considered for autologous stem cell transplantation. Bone marrow aspirate showed 90% plasma cells. Bone marrow biopsy showed a predominant population of λ light chain–restricted plasma cells, consistent with multiple myeloma. Congo red stains on the bone marrow biopsy specimen were negative for amyloid. The patient was referred to an academic medical center and was being considered for autologous stem cell transplantation. DiscussionWe present a case of acute kidney injury in a 59-year-old woman who presented to the emergency department with backaches and numbness and tingling of her limbs. Subsequent workup showed multiple myeloma with extensive involvement of the skeletal system. The initial clinical impression of the acute kidney injury was that of myeloma kidney (cast nephropathy) or interstitial nephritis secondary to nonsteroidal anti inflammatory drug use. Kidney biopsy specimens showed features of cast nephropathy with PAS- and silver-negative casts with a fractured appearance surrounded by an interstitial infiltrate. The diagnosis of cast nephropathy was confirmed on immunofluorescence microscopy, in which many casts stained for λ light chains, but were negative for κ light chains. However, the case was unusual in that some casts did not appear to be histologically like those in cast nephropathy, although they elicited an inflammatory reaction around them. These casts were PAS and silver positive, appeared lamellated with a central necrotic nidus, and some casts showed distinct spicule formation on their periphery. In addition, casts were much larger, did not have a fractured appearance, and showed bright apple green birefringence on Congo red stains, suggesting they were made of amyloid fibrils. Electron microscopy confirmed that these casts were made of amyloid fibrils.Amyloid can be found anywhere in the kidney, but glomerular deposition typically predominates. By using light microscopy, glomerular amyloid appears as amorphous material in the mesangium and capillary loops. Mesangial involvement usually leads to the formation of PAS-negative mesangial nodules. Glomerular capillary walls are infiltrated with amyloid, resulting in thickening of glomerular basement membranes. On silver stains, spicules can be seen at the periphery of the amyloid material both in the mesangium and along capillary walls. When the glomerulus is involved, almost 50% of patients present with reduced glomerular filtration rate and more than 70% have proteinuria. Vessels also are commonly involved, initially in the media. Less commonly, amyloid deposits in the tubular basement membrane lead to tubular atrophy and interstitial fibrosis. When amyloid is confined to the tubulointerstitium or vasculature, a concentrating defect may be present, and proteinuria is minimal and reduced glomerular filtration rate is the principal clinical manifestation.2Dember L.M. Amyloidosis-associated kidney disease.J Am Soc Nephrol. 2006; 17: 3458-3471Crossref PubMed Scopus (265) Google Scholar, 3Kyle R.A. Greipp P.R. Amyloidosis (AL) Clinical and laboratory features in 229 cases.Mayo Clin Proc. 1983; 58: 665-683PubMed Google Scholar, 4Gertz M.A. Lacy M.Q. Dispenzieri A. Amyloidosis: Recognition, confirmation, prognosis, and therapy.Mayo Clin Proc. 1999; 74: 490-494PubMed Scopus (99) Google ScholarA search of the literature showed 3 reports of amyloid casts in tubules.5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar, 6El-Zoghby Z. Lager D. Gregoire J. Lewin M. Sethi S. Intra-tubular amyloidosis.Kidney Int. 2007; 72: 1282-1288Crossref PubMed Scopus (23) Google Scholar, 7Friman C. Tornroth T. Wegelius O. IgD myeloma associated with multiple extramedullary amyloid-containing tumours and amyloid casts in the renal tubules.Ann Clin Res. 1970; 2: 161-166PubMed Google Scholar Melato et al5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar examined 30 autopsy specimens from patients who had multiple myeloma or monoclonal gammopathy of undetermined significance. They found 4 cases of renal tubular casts showing histochemical characteristics of immunoamyloid. All patients had multiple myeloma with light chains in urine. No case of monoclonal gammopathy had tubular amyloid casts.5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar The diagnosis of tubular amyloid casts was based on Congo red stains. Because tissue was obtained from autopsy specimens, immunofluorescence and electron microscopy were not carried out. El-Zoghby et al6El-Zoghby Z. Lager D. Gregoire J. Lewin M. Sethi S. Intra-tubular amyloidosis.Kidney Int. 2007; 72: 1282-1288Crossref PubMed Scopus (23) Google Scholar also reported a case of intratubular amyloid casts in a patient with multiple myeloma. The case is similar to our case in that amyloid casts were noted in tubules, whereas glomeruli and vessels did not show amyloid. Friman et al7Friman C. Tornroth T. Wegelius O. IgD myeloma associated with multiple extramedullary amyloid-containing tumours and amyloid casts in the renal tubules.Ann Clin Res. 1970; 2: 161-166PubMed Google Scholar reported a case of immunoglobulin D myeloma associated with multiple extramedullary amyloid-containing tumors and amyloid casts in renal tubules.Differential diagnosis of casts in a setting of multiple myeloma includes: (1) myeloma casts: fractured casts of myeloma kidney/cast nephropathy as described; (2) hyaline casts: these casts are PAS and silver positive, often present in tubules in scarred areas, do not show a preference for κ or λ light chains, and often stain for immunoglobulin A on immunofluorescence microscopy; they do not elicit an inflammatory reaction; (3) Tamm-Horsfall protein casts: often seen in the setting of obstruction, with leakage of casts into the interstitium with localized inflammatory infiltrates; (4) light chain crystal casts: often seen in patients with Fanconi syndrome or crystal-storing histiocytosis,8Sethi S. Cuiffo B. Pinkus G. Rennke H. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder.Am J Kidney Dis. 2002; 39: 183-188Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar casts are PAS positive and have needle, rectangular, or rhomboid appearance; are present in tubular lumen and tubular epithelial cells; and stain for either λ or κ light chains on immunofluorescence microscopy; and (5) AL amyloid casts: casts are PAS and silver negative, may have spicule formation at the rims, are Congo red positive, and electron microscopy confirms the diagnosis (Table 2).Table 2Casts in Multiple MyelomaMyeloma castsFractured appearance, PAS and silver negative, surrounded by inflammatory infiltrate, positive for either κ or λ light chainsHyaline castsHomogenous appearance, PAS and silver positive, often present in scarred areas, stain for polyclonal IgATamm-Horsfall protein castsLarge amorphous-appearing, tubular disruption leads to leakage of casts into interstitium and localized inflammatory infiltrates, PAS positive or negative, polyclonalLight chain crystal castsNeedle, rectangular, or rhomboid appearance; PAS positive; present in tubular lumen and tubular epithelial cells; positive for either λ or κ light chainsLight chain amyloid castsMay have spicule formation at rims with necrotic center, PAS and silver negative, Congo red positive, positive for either κ or λ light chains, electron microscopy confirms diagnosisAbbreviations: IgA, immunoglobulin A; PAS, periodic acid–Schiff. Open table in a new tab The pathophysiological process of intratubular amyloid is unclear because amyloid fibrils are large and likely not filtered through the glomerular basement membrane. One has to assume that fibrils are formed inside the tubule from either protein secreted by tubular cells or filtered light chains. The latter is more likely because it is the mechanism by which intratubular casts are formed in patients with multiple myeloma.9Sanders P.W. Herrera G.A. Monoclonal immunoglobulin light chain-related renal diseases.Semin Nephrol. 1993; 13: 324-341PubMed Google Scholar, 10Palladini G. Lavatelli F. Russo P. et al.Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL.Blood. 2006; 107: 3854-3858Crossref PubMed Scopus (220) Google ScholarTo summarize, we present an interesting case of multiple myeloma with features of both cast nephropathy and tubular amyloid casts. Although cast nephropathy with glomerular amyloid has been described, the presentation of both myeloma casts and tubular amyloid casts together is unusual. Amyloid casts should be considered when differentiating casts in a setting of multiple myeloma. We present a case of acute kidney injury in a 59-year-old woman who presented to the emergency department with backaches and numbness and tingling of her limbs. Subsequent workup showed multiple myeloma with extensive involvement of the skeletal system. The initial clinical impression of the acute kidney injury was that of myeloma kidney (cast nephropathy) or interstitial nephritis secondary to nonsteroidal anti inflammatory drug use. Kidney biopsy specimens showed features of cast nephropathy with PAS- and silver-negative casts with a fractured appearance surrounded by an interstitial infiltrate. The diagnosis of cast nephropathy was confirmed on immunofluorescence microscopy, in which many casts stained for λ light chains, but were negative for κ light chains. However, the case was unusual in that some casts did not appear to be histologically like those in cast nephropathy, although they elicited an inflammatory reaction around them. These casts were PAS and silver positive, appeared lamellated with a central necrotic nidus, and some casts showed distinct spicule formation on their periphery. In addition, casts were much larger, did not have a fractured appearance, and showed bright apple green birefringence on Congo red stains, suggesting they were made of amyloid fibrils. Electron microscopy confirmed that these casts were made of amyloid fibrils. Amyloid can be found anywhere in the kidney, but glomerular deposition typically predominates. By using light microscopy, glomerular amyloid appears as amorphous material in the mesangium and capillary loops. Mesangial involvement usually leads to the formation of PAS-negative mesangial nodules. Glomerular capillary walls are infiltrated with amyloid, resulting in thickening of glomerular basement membranes. On silver stains, spicules can be seen at the periphery of the amyloid material both in the mesangium and along capillary walls. When the glomerulus is involved, almost 50% of patients present with reduced glomerular filtration rate and more than 70% have proteinuria. Vessels also are commonly involved, initially in the media. Less commonly, amyloid deposits in the tubular basement membrane lead to tubular atrophy and interstitial fibrosis. When amyloid is confined to the tubulointerstitium or vasculature, a concentrating defect may be present, and proteinuria is minimal and reduced glomerular filtration rate is the principal clinical manifestation.2Dember L.M. Amyloidosis-associated kidney disease.J Am Soc Nephrol. 2006; 17: 3458-3471Crossref PubMed Scopus (265) Google Scholar, 3Kyle R.A. Greipp P.R. Amyloidosis (AL) Clinical and laboratory features in 229 cases.Mayo Clin Proc. 1983; 58: 665-683PubMed Google Scholar, 4Gertz M.A. Lacy M.Q. Dispenzieri A. Amyloidosis: Recognition, confirmation, prognosis, and therapy.Mayo Clin Proc. 1999; 74: 490-494PubMed Scopus (99) Google Scholar A search of the literature showed 3 reports of amyloid casts in tubules.5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar, 6El-Zoghby Z. Lager D. Gregoire J. Lewin M. Sethi S. Intra-tubular amyloidosis.Kidney Int. 2007; 72: 1282-1288Crossref PubMed Scopus (23) Google Scholar, 7Friman C. Tornroth T. Wegelius O. IgD myeloma associated with multiple extramedullary amyloid-containing tumours and amyloid casts in the renal tubules.Ann Clin Res. 1970; 2: 161-166PubMed Google Scholar Melato et al5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar examined 30 autopsy specimens from patients who had multiple myeloma or monoclonal gammopathy of undetermined significance. They found 4 cases of renal tubular casts showing histochemical characteristics of immunoamyloid. All patients had multiple myeloma with light chains in urine. No case of monoclonal gammopathy had tubular amyloid casts.5Melato M. Falconieri G. Pascali E. Pezzoli A. Amyloid casts within renal tubules: A singular finding in myelomatosis.Virchows Arch A Pathol Anat Histol. 1980; 387: 133-145Crossref PubMed Scopus (15) Google Scholar The diagnosis of tubular amyloid casts was based on Congo red stains. Because tissue was obtained from autopsy specimens, immunofluorescence and electron microscopy were not carried out. El-Zoghby et al6El-Zoghby Z. Lager D. Gregoire J. Lewin M. Sethi S. Intra-tubular amyloidosis.Kidney Int. 2007; 72: 1282-1288Crossref PubMed Scopus (23) Google Scholar also reported a case of intratubular amyloid casts in a patient with multiple myeloma. The case is similar to our case in that amyloid casts were noted in tubules, whereas glomeruli and vessels did not show amyloid. Friman et al7Friman C. Tornroth T. Wegelius O. IgD myeloma associated with multiple extramedullary amyloid-containing tumours and amyloid casts in the renal tubules.Ann Clin Res. 1970; 2: 161-166PubMed Google Scholar reported a case of immunoglobulin D myeloma associated with multiple extramedullary amyloid-containing tumors and amyloid casts in renal tubules. Differential diagnosis of casts in a setting of multiple myeloma includes: (1) myeloma casts: fractured casts of myeloma kidney/cast nephropathy as described; (2) hyaline casts: these casts are PAS and silver positive, often present in tubules in scarred areas, do not show a preference for κ or λ light chains, and often stain for immunoglobulin A on immunofluorescence microscopy; they do not elicit an inflammatory reaction; (3) Tamm-Horsfall protein casts: often seen in the setting of obstruction, with leakage of casts into the interstitium with localized inflammatory infiltrates; (4) light chain crystal casts: often seen in patients with Fanconi syndrome or crystal-storing histiocytosis,8Sethi S. Cuiffo B. Pinkus G. Rennke H. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder.Am J Kidney Dis. 2002; 39: 183-188Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar casts are PAS positive and have needle, rectangular, or rhomboid appearance; are present in tubular lumen and tubular epithelial cells; and stain for either λ or κ light chains on immunofluorescence microscopy; and (5) AL amyloid casts: casts are PAS and silver negative, may have spicule formation at the rims, are Congo red positive, and electron microscopy confirms the diagnosis (Table 2). Abbreviations: IgA, immunoglobulin A; PAS, periodic acid–Schiff. The pathophysiological process of intratubular amyloid is unclear because amyloid fibrils are large and likely not filtered through the glomerular basement membrane. One has to assume that fibrils are formed inside the tubule from either protein secreted by tubular cells or filtered light chains. The latter is more likely because it is the mechanism by which intratubular casts are formed in patients with multiple myeloma.9Sanders P.W. Herrera G.A. Monoclonal immunoglobulin light chain-related renal diseases.Semin Nephrol. 1993; 13: 324-341PubMed Google Scholar, 10Palladini G. Lavatelli F. Russo P. et al.Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL.Blood. 2006; 107: 3854-3858Crossref PubMed Scopus (220) Google Scholar To summarize, we present an interesting case of multiple myeloma with features of both cast nephropathy and tubular amyloid casts. Although cast nephropathy with glomerular amyloid has been described, the presentation of both myeloma casts and tubular amyloid casts together is unusual. Amyloid casts should be considered when differentiating casts in a setting of multiple myeloma. Support: None. Financial Disclosure: None.